Stable aqueous solutions of anaesthetic substances



Patented Sept. 18, 1934 UNI-TED" S TATES PATENT OFFICE STABLE sermons SOLUTIONS OF ANESTHETIC snnsmnons Max Bockmiihl and Willy Ludwig, Frankfort-onv the-Main, Germany, assignors" to Winthrop Chemical Company, New York, N. Y., a corporation of New York No. Drawing. Application December 16, 1932,

- Serial No. 64 7,695. In Germany. December 1'7,,

cosity-of theaqueous solution; which; is due to the,

addition of the colloid renders the solution sui t able for lumbar anesthesia. Whereasit is possible according to this method-to prepare a solution containing,.for instance, 40% of the hydrochloride of para-aminobenzoic acid diethylarnino 'ethylester, it has been found that when the said process is applied to, the .alkamine -esters of N-monoalkylated. and Namonoalkyloxyalkylated derivatives of. para-and orthoaminobenz oic acid described in EislebsU. S. Patents Nos. 1-,550,350 dated August 18, 1925 and 1,7 0 4,66Q dated March 5, 1929 the comparatively great solubilityin,

Water of, for instance, the hydrochlorides 'OIfSlll fates of the said substances is extremely diminished. Thus, for instance, the solubility of the hydrochloride of para-butylaminoloenzoic acid dimethylaminoethylester is reduced from about 15% to less than 0.5% and, consequently, is no longer suificient for the purposes of lumbar anaesthesia.

Now, we have found that aqueous solutions of anaesthetic substances comprising a prolamine, wheat mucilage and a salt of an organic hydroxylated carboxylic acid with a compound of the following formula:

CIEOORI wherein R1 stands for an alkamine group, one X for hydrogen, the other X for the group -NI-I.R2, R2; being an alkyl or an alkyl-alkyloxy group, are stable and highly viscous.

It could in no way be foreseen that the said alkamine-esters in the form of their salts with aliphatic or hydroaromatic hydroxy acids would of aprimary, and in the other case in the presence 1 6 claims. (o1. 167 52) used could in no way be concluded fromthe known process of preparing solutions of the hydrochloride of the said ethylester. The fact that, as above mentioned, the hydrochlorides of the two esters physically behave totally differently from each-other can only be explained by the different chemical cohstitutio'n'bf the two bodies which manifests'itself in the one-case in the presence of a secondary aromaticamino group. Thisdifference of constitution is not only the cause of the .different physical properties of the compounds but also of the-quantitative and qualitative difjference' in the physiologic. action of thebodies insofar as the para-aminobenzoic acid diethyl-" aminoethylester is'a conductive anaesthetic and the alkamine esters used according to the present invention are moreover andiin the first line agents for producing surface anaesthesia. The two compounds belong to different classes of bodies so that the behaviour of the one body could 'not be concluded from the behaviour of the other body.

The enhanced solubility of the alkamine esters in the form of their salts of hydroxyacids is not only inherent to the solutions immediately after their preparation. Even after a prolonged time the solutions show an unaltered stability. They may be sterilized by heating to 100 C.

According to the present invention, it is advantageous to prepare at first a solution of the colloid of suitable concentration and to add thereafter the alkarnine ester in the form of a salt. It is also possible to dissolve the anaesthetic substance simultaneously with the necessary quantity of colloid. There may also be added to the solutions additional substances such as preserving agents or the like.

As anaesthetic substances there may be used, for instance, the products described in U. S. Pat- 95 ents No. 1,550,350 and No. 1,889,645. As hydroxylated carboxylic acids there may be used aliphatic compounds such as citric acid, glycollic acid, lactic acid, or hydroaromatic compounds such as quinic acid.

The following examples serve to illustrate the invention but they are not intended to limit it thereto:

(1) 25 grams of d-butylaminobenzoic acidbeta-dimethylaminoethylester are converted into the salt of quinic acid by means of 18.75 grams of quinic acid in 470 cc. of water; there are subsequently added 200 cc. of wheat mucilage (0.75% dry residue) 250 cc. of alcohol and 40.6 cc. of gliadinal alcohol (3% of dry residue). The

are heated on the steam bath for 30 minutes with my;

1.9 grams of quinic acid in 45 cc. of water. There 2. Aqueous solutions of anaesthetic substances comprising a prolamine, wheat mucilage and a salt of an acid of the group consisting of hydro- --;aromatic-. a-nd aliphatic hydroxy-lated carboxylic acidsilwith aicompoundlof theafollowingrformulaz COOR:

are subsequently added 20 cc. of WheatQmuoilagey 25 cc. of alcohol and 4 cc. of gliadina'1*alcohol;--'

the whole is then made up to 3.00 cc=by meansrof a distilled Water. The solutiontisfiltered andEiur-l ther treated as indicated in Example 14..

(3) 2.8 grams of 2-N-propylaminobenzoic acid beta diethylaminoethylester .(base) area tvhereinjRrestandszforan alkamine group, one X for hydrogen, the; other X for the group-NH.R2, R2 being an alkyl or an alkyl-alkyloxy group.

heated on the steam bath for 30 minuteswith 2111; r; AquePus Solutions of anaesthetic substances grams of citric acid in 45 cc. of water. There are added subsequently 20 cc. of wheat mucilage and 4 cc. of gliadinal alcohol. Thereafter, the

comprising a-prolamine; wheat mucilage and a salt of an acid of thegroup consisting of hydroaromatic andaliphatic hydroxylated carboxylic whcleismade-up to 300cc. by means of: distilled esai with alcompolmd theionowing'f'ormulai'c water and the solution-is fiurthervtreatedas in Example 11-;

ooom- (4) 2.8 gramsyof 4-propylaminobenzoic';acid? 1,- dimethylaminobutyl -3,-ester= are gently heated with a compoundyof the-"following formulax pg o o 0 B1 at 30 C. with 0.8 gramaof g-lycoll-icacid in 45 cc.-

an alkyl group 4. An aqueous-solutiomoi an anaesthetic sub wherein R1 "stands for an alkamine group, R2 for stance comprisinggliadinatl-alcohol,-Wheat-muci- Agtleousflsolumo-lts of anwsthetlc. lage' and the salt of 4-butylam'inobenzoic-acid-= compl'lsmgi Q wheahmuclla'gefandlfii beta-dimethylaminoethylesterwith*quinio acid. saltof an \orgammhydroxylated carboxylic ac1dz;..:: 5. An aqueouslsolutionofanaestheticisubstance the "salt- 6f o-N-propylaminobenzoic acid-beta diethylaminoeth-ylester'=with citric acid:

6. An'aqueous-solution ofan --*amesthetic'-sub--- stance comprising gliadinaalcohol, wheat muci lageandthe salt of 4-5propy'lami-nobenzoio acid- 1-dimethylaminobutyl-fi -ester with glycollic acid:

wherein R1, stands for an alkamine group',*one X for hydrogen, the other X for 'theigroup NHtRz;' R2 being an alkyl'or an alkyl alkyloxy groin):

comprisinggliadirie alcohol; wheat-mucilag-e and 

